CLINICAL STUDIES
Augmentation of the cardiac natriuretic peptides by beta-receptor antagonism: evidence from a population-based study
Andreas Luchner, MDa,
John C. Burnett, Jr., MD*,
Michihisa Jougasaki, MD, PhD*,
Hans-Werner Hense, MD  ,
G.ünter A. J. Riegger, MDa and
Heribert Schunkert, MDa
a Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Regensburg, Germany
* Cardiorenal Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA
GSF-Institut für Epidemiologie, Munich, Germany
Institut für Epidemiologie und Sozialmedizin, University of Münster, Münster, Germany
Manuscript received January 14, 1998;
revised manuscript received July 24, 1998,
accepted August 20, 1998.
Address for correspondence: Dr. Heribert Schunkert, Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany
heribert.schunkert{at}klinik.uni-regensburg.de
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Abstract
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Objectives. The present retrospective analysis of data derived from a population-based study examined the relationship between intake of beta-receptor antagonists and plasma concentrations of the cardiac natriuretic peptides and their second messenger.
Background. Beta-receptor antagonists are widely used for treatment of cardiovascular disease. In addition to direct effects on heart rate and cardiac contractility, recent evidence suggests that beta-receptor antagonists may also modulate the cross talk between the sympathetic nervous system and the cardiac natriuretic peptide system.
Methods. Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their second messenger cyclic guanosine monophosphate (cGMP) were assessed in addition to anthropometric, hemodynamic and echocardiographic parameters in a population-based sample (n = 672), of which 80 subjects used beta-receptor antagonists.
Results. Compared to subjects without medication, subjects receiving beta-receptor antagonists were characterized by substantially elevated ANP, BNP and cGMP plasma concentrations (plus 32%, 89% and 18%, respectively, p < 0.01 each). Analysis of subgroups revealed that this effect was highly consistent and present even in the absence of hypertension, left atrial enlargement, left ventricular hypertrophy or left ventricular dysfunction. The most prominent increase was observed in a subgroup with increased left ventricular mass index. By multivariate analysis, a statistically significant and independent association between beta-receptor antagonism and ANP, BNP and cGMP concentrations was confirmed. Such an association could not be demonstrated for other antihypertensive agents such as angiotensin-converting enzyme inhibitors or diuretics.
Conclusions. Beta-receptor antagonists appear to augment plasma ANP, BNP and cGMP concentrations. The current observation suggests an important contribution of the cardiac natriuretic peptide system to the therapeutic mechanism of beta-receptor antagonists.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme inhibition | | ANP | = atrial natriuretic peptide | | BNP | = brain natriuretic peptide | | cGMP | = cyclic guanosine monophosphate | | EDD | = end diastolic diameter | | FS | = fractional shortening | | LVM | = left ventricular mass | | LVMI | = left ventricular mass index |
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Beta-receptor antagonists are widely used in the treatment of arterial hypertension and coronary artery disease (1,2). More recently, beneficial effects have also been demonstrated in patients with heart failure, including marked improvement in cardiac function (3–7), and most importantly, a reduction in mortality (8,9). While the pharmacodynamic mechanisms underlying the antihypertensive and anti-ischemic actions of beta-receptor antagonists may be sufficiently explained by direct inhibition of cardiac catecholamine effects with subsequent negative inotropy and chronotropy, the mechanisms responsible for beneficial actions in heart failure are less clear.
In addition to effects on heart rate and cardiac contractility, stimulation of beta-adrenergic receptors also leads to interactions with other neurohormonal systems. The existence of such an interaction between the beta-adrenergic system and the natriuretic peptide system has been proposed by experimental studies which reported the suppression of cardiac atrial natriuretic peptide (ANP)-release in response to beta-adrenergic stimulation (10,11). Interactions between the beta-adrenergic and natriuretic peptide systems have also been studied in patients with hypertension (12,13). An inverse relation between beta-adrenergic and natriuretic peptide systems was demonstrated with beta-receptor antagonism, resulting in elevated concentrations of plasma ANP; however, these studies were short-term trials and included only small groups of hypertensive patients without control for hemodynamic or cardiac structural parameters. Furthermore, it remained unclear whether beta-receptor antagonism also affects the second member of the cardiac natriuretic peptide system, brain natriuretic peptide (BNP).
The current study was therefore undertaken to further investigate the association between beta-receptor antagonism and ANP, BNP and their second messenger, cyclic guanosine monophosphate (cGMP), in a population-based sample. We hypothesized that beta-receptor antagonism would be associated with a significant, independent augmentation of all members of the cardiac natriuretic peptide system.
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Methods
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Study population.
The subjects of this study had initially participated in the MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) baseline survey of 1984/85 and its follow-up examination in 1987/88. Subjects originate from a sex-age-stratified random sample of all German residents of the Augsburg study area. In 1994, a second follow-up examination including biochemical and anthropometric measurements was offered to a total of 1,010 men and women, aged 50 to 67 years, of whom 672 participated (14). All subjects provided information on medical history, physical activities, medication, and personal habits. The information on drug therapy was verified by inspection of medication forms or medications brought to the study center. Body height and weight were recorded in light clothing, and body mass index was computed as weight in kg divided by height in meter squared (kg·m–2). Resting blood pressure was measured three times and the mean used for the study. Arterial hypertension was defined as blood pressure equal or above 160/95 mmHg and normotension was defined as blood pressure below 140/90 mmHg.
Echocardiography.
A two-dimensionally guided M-mode echocardiogram was performed on each subject by one of two expert sonographers (Sonos 1500, Hewlett Packard, Avondale, Pennsylvania). M-mode tracings were recorded on stripchart paper at 50 mm·s–1. Only tracings that demonstrated optimal visualization of left ventricular interfaces were used. To reduce interobserver variability, all M-mode tracings were analyzed by a single cardiologist who was blinded for the clinical and biochemical data. Measurements for M-mode-guided calculation of left ventricular mass were taken just below the tip of the mitral valve. Left ventricular internal end diastolic (EDD) and end systolic diameters (ESD) and septal (Swth) and posterior wall thickness (Pwth) were measured according to the guidelines of the American Society of Echocardiography (15). Fractional shortening (FS) as a measure of left ventricular function was calculated as:
 | (1) |
Left ventricular mass (LVM) was calculated from M-mode echocardiograms according to the formula described by Devereux et al. (16):
 | (2) |
Left ventricular mass was indexed to body surface area as left ventricular mass index (LVMI) in g m–2 body surface area.
Left ventricular hypertrophy by M-mode criteria was designated when left ventricular mass index was greater than 134 g·m–2 body surface area in men and greater than 110 g·m–2 body surface area in women (16). Left atrial enlargement was designated when left atrial diameter was greater than 45 mm. Systolic left ventricular dysfunction was designated when fractional shortening was below 28%.
Biochemical measurements.
Blood drawn after subjects were in supine resting position for at least 30 min was immediately chilled and centrifuged. The plasma was stored at –80°C. ANP, BNP, and cGMP were measured by standard radioimmunoassay techniques with all determinations performed in duplicate. For measurement of ANP, plasma was preacidified with acetic acid, extracted on prewashed C-18 columns (Sep-Pak, Waters, Milford, Massachusetts) washed with Tris-HCl, eluted with acetonitril|ammonium acid and measured with a commercially available antibody (Amersham, Buckinghamshire, United Kingdom). BNP was measured with a commercially available RIA-kit (Shionogi, Osaka, Japan) without cross-reactivity to ANP (17). cGMP was measured after methanol extraction by a commercially available kit (NEN, Boston, Massachusetts).
Statistics.
The statistical significance of differences in mean ANP and cGMP concentrations between subjects with and without beta-receptor antagonists was calculated by the unpaired t test. Since BNP was not normally distributed, differences in mean BNP concentrations were compared by the Mann Whitney U test. Subgroups classified according to arterial blood pressure, concomitant antihypertensive therapy, left atrial diameter, left ventricular mass index, and left ventricular function were compared with the same respective tests. Testing of subgroups was intended to minimize the risk of attributing differences between groups to treatment with beta-receptor antagonists rather than to potential specific confounders (i.e., bias by treatment indication). Confounders which often lead to treatment with beta-receptor antagonists are arterial hypertension, cardiac hypertrophy and, more recently, left ventricular dysfunction. Further statistical testing was performed employing univariate and multivariate analysis. Multivariate analysis was performed to determine whether beta-receptor antagonism was a statistically independent predictor of the cardiac natriuretic peptide system. These tests were performed with ANP, BNP, log (BNP) and cGMP as dependent variables. Together with the multivariate correlation coefficients, the corresponding beta coefficients were computed. The beta coefficient is an adjusted measure for the magnitude of change that can be attributed to a given change in the corresponding predictor. P-values below 0.05 were defined as statistically significant and p-values below 0.01 as highly significant.
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Results
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Characterization of study population.
Of the 672 subjects, 80 were treated with beta-receptor antagonists. The different types of beta-receptor antagonists and the mean doses used are listed in Table 1. Overall, the prescribed mean dose was 42% of the recommended maximal dose. Anthropometric, hemodynamic, and echocardiographic characteristics as well as the relevant medical history of the studied population are listed in Table 2. No significant differences between subjects with and without beta-receptor antagonists were found with respect to gender distribution, body mass index, history of diabetes or myocardial infarction and left ventricular function; however, subjects receiving beta-receptor antagonists were slightly older and were characterized by lower heart rate, higher systolic and diastolic blood pressure, greater left atrial diameter and higher left ventricular mass index. Subjects treated with beta-receptor antagonists more often received concomitant diuretic therapy or other antihypertensive therapy but there was no difference in the use of angiotensin-converting enzyme inhibitors between groups.
Cardiac natriuretic peptide system and treatment with beta-receptor antagonists.
As compared to untreated individuals, ANP, BNP and cGMP were highly significantly elevated in subjects treated with beta-receptor antagonists (Fig. 1). Specifically, ANP was increased by 32% while BNP was increased by 89% and cGMP was increased by 18%.
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Figure 1 Atrial natriuretic peptide, brain natriuretic peptide, and cyclic guanosine monophosphate plasma concentrations were significantly elevated in subjects with (black bars) as compared to those without (hatched bars) beta-receptor antagonism. Differences between groups may be overestimated by confounding variables (Table 2). ANP and BNP were in pg·ml–1 and cGMP in pmol·ml–1. **p < 0.01 vs. subjects without beta-receptor antagonism.
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Subgroup analysis.
This association was further studied in a number of subgroups (Fig. 2). An augmentation of the cardiac natriuretic peptides in subjects treated with beta-receptor antagonists was observed in the presence and absence of hypertension, in the absence of concomitant antihypertensive therapy, in the presence and absence of left ventricular hypertrophy and in the absence of left atrial distention and left ventricular dysfunction. The greatest increase was observed in subjects with left ventricular hypertrophy (ANP + 36% and BNP + 121%). A strong tendency toward increased concentrations of BNP in a small subgroup of subjects with left atrial distention and treatment with beta-receptor antagonists did not reach statistical significance, most likely due to the small sample size (n = 11). An increase in ANP by 22% and BNP by 32% in a small subgroup (n = 10) of subjects with left ventricular dysfunction and treatment with beta-receptor antagonists also did not reach statistical significance.
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Figure 2 Subgroup analysis for ANP and BNP plasma concentrations in subjects with (black bars) and without (hatched bars) beta-receptor antagonism. RR = arterial blood pressure; Rx = antihypertensive therapy; LAd = left atrial diameter; LVMI = left ventricular mass index; LV-fct. = left ventricular function. *p < 0.05 vs. subjects without beta-receptor antagonism, **p < 0.01 vs. subjects without beta-receptor antagonism.
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Univariate analysis.
By univariate analysis, ANP, BNP and cGMP concentrations were positively correlated with a number of anthropometric and cardiac structural and functional parameters (Table 3).
Multivariate analysis.
For multivariate analysis (Table 4), therapy with beta-receptor antagonists was included into a multivariate regression model together with the previously identified predictors as well as angiotensin-converting enzyme inhibitor therapy, diuretic therapy and therapy with other antihypertensive agents. Information regarding potential predictors, including all mentioned echocardiographic parameters, was complete for 462 subjects.
Beta-receptor antagonist therapy was found to be a significant predictor of ANP, BNP, log (BNP) and cGMP concentrations by multivariate analysis. In contrast, neither medication with angiotensin-converting enzyme inhibitors, diuretics or other antihypertensive therapies was found to be significantly correlated with ANP, BNP, log (BNP) or cGMP plasma concentrations. Based upon the beta-coefficient, the absolute increase that appears to be attributed to therapy with beta-receptor antagonists was 11.2 pg·ml–1 for ANP, 13.9 pg·ml–1 for BNP and 0.56 pmol·ml–1 for cGMP. These absolute increases correspond to relative increases of +21%, +82% and +17% for ANP, BNP and cGMP, respectively.
In multivariate analysis, systolic blood pressure and left ventricular mass index were not confirmed as independent predictors of ANP, left atrial diameter was not confirmed as an independent predictor of BNP and systolic blood pressure was not confirmed as an independent predictor of cGMP.
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Discussion
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The objective of the current study was to investigate the relationship between beta-receptor antagonism and the cardiac natriuretic peptide system in a population-based study. A marked elevation of circulating ANP, BNP and cGMP concentrations in subjects treated with beta-receptor antagonists was observed. Further analysis revealed that this effect was highly reproducible in a number of different subgroups, independent of potential confounders, and most prominent in subjects with left ventricular hypertrophy; thus, the current findings suggest that chronic treatment with beta-receptor antagonists may lead to an augmentation of ANP and BNP and that this activation is functionally relevant because it is associated with increased concentrations of cGMP, the second messenger of the natriuretic peptide system. Given the benefits of an augmented natriuretic peptide system, it may further be speculated that this effect may contribute to the therapeutic action of beta-receptor antagonists, particularly in left ventricular hypertrophy and, possibly, in left ventricular dysfunction.
Potential mechanisms and therapeutic implications.
The present observations appear highly plausible based on in vivo and in vitro studies which have established important interactions between adrenergic receptor signaling and the synthesis and release of cardiac natriuretic peptides. In particular, inhibition of the cardiac natriuretic peptides has been described in response to beta-adrenergic stimulation. Specifically, beta-adrenergic stimulation reduced ANP secretion in cultured myocytes (18) and in vivo, beta-adrenergic stimulation decreased ANP when isoproterenol was infused locally into coronary arteries of pigs to stimulate left atrial adrenoceptors without concomitant changes in atrial filling pressures (10,11). In contrast, stimulation of the alpha receptor has been shown to increase ANP secretion in pigs (10,11) and cultured myocytes (18–20), and a stimulatory alpha 1-adrenergic regulatory sequence has been identified in the 5' flanking region of the ANP gene (21). Such a stimulatory effect has also been described for BNP in a study which reported stabilization of BNP mRNA through alpha-adrenergic activation (22). These experimental data on differential effects of adrenergic receptors on the cardiac natriuretic peptides may help to explain the current findings as they emphasize potential effects of beta-adrenergic receptor antagonists on the balance between alpha- and beta-adrenergic stimulation which is critical for the regulated secretion of the cardiac natriuretic peptides.
It is tempting to speculate that beta-receptor antagonism-related augmentation of natriuretic peptides offers a yet unrecognized therapeutic mechanism for this class of drugs. This notion is underscored by the elevation of cGMP, the second messenger for both ANP and BNP. Indeed, exogenous infusion of ANP and BNP has been demonstrated to result in vasodilatation, natriuresis and diuresis, improved central hemodynamics and left ventricular diastolic function (23–25). Beneficial effects of an augmented natriuretic peptide system might also involve the suppression of the renin angiotensin (26,27) and endothelin systems (28) as well as vascular and cardiac antihypertrophic effects (29,30). Indeed, these mechanisms may be particularly beneficial in patients with congestive heart failure. In the current study population, only a small subgroup was characterized by left ventricular dysfunction; however, these subjects, when treated with beta-receptor antagonists, were characterized by an increase in ANP by 22% and BNP by 32% as compared to subjects with left ventricular dysfunction not receiving such treatment. This finding should be further evaluated in a prospective trial in patients with congestive heart failure.
Study design.
The current observational study harbors a potential for bias by treatment indication because beta-receptor antagonists are often prescribed in the presence of factors which can affect cardiac natriuretic peptide concentrations by themselves, particularly cardiac hypertrophy and left ventricular dysfunction (31–34). To address this issue, we employed three strategies. First, the association between beta-receptor antagonism and natriuretic peptides in a number of subgroups was studied. In fact, beta-receptor antagonism was consistently associated with elevated ANP and BNP concentrations even in the absence of hypertension, left ventricular hypertrophy, or left ventricular dysfunction. Next, this association was examined in a multivariate regression model that included a series of potential confounders. Beta-receptor antagonism still remained an independent and significant predictor of ANP, BNP and cGMP concentrations, and the relative increases which appeared to be attributed to therapy with beta-receptor antagonists were +21%, +82%, and +17% for ANP, BNP and cGMP, respectively. Finally, when compared with angiotensin-converting enzyme inhibition and diuretic therapy, the augmentation of ANP, BNP and cGMP was specific for beta-receptor antagonism. In conjunction, recent experimental data and the present analyses suggest that the elevation of ANP, BNP and cGMP concentrations is directly related to beta-receptor antagonism; nevertheless, given the design of our study, this observation should be confirmed in prospective placebo-controlled trials.
Conclusions.
The current study provides new insights into the interplay between the beta-adrenergic and the cardiac natriuretic peptide system. ANP, BNP and cGMP concentrations appear to be substantially augmented by use of beta-receptor antagonists, independently of anthropometric parameters, cardiac structure, and function. The current data suggest a possible contribution of the natriuretic peptide system to the therapeutic spectrum of beta-receptor antagonism.
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Acknowledgments
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The authors acknowledge outstanding support by Michael Muscholl, MD and Susanne Kürzinger, BS.
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Footnotes
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG Lu 562/1-1, 2 and 2-1 and Schu 672/3-1, 9-1 and 10-1), the Bundesministerium für Forschung und Technologie (H.S. and H.-W.H.) and by grants from the National Institutes of Health (HL-36634 and HL-07111) and the Mayo Foundation.
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M. Kuhn, M. Voss, D. Mitko, J. Stypmann, C. Schmid, N. Kawaguchi, F. Grabellus, and H. A. Baba
Left ventricular assist device support reverses altered cardiac expression and function of natriuretic peptides and receptors in end-stage heart failure
Cardiovasc Res,
November 1, 2004;
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A Luchner and H Schunkert
Interactions between the sympathetic nervous system and the cardiac natriuretic peptide system
Cardiovasc Res,
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J. P. Goetze, W. Yongzhong, J. F Rehfeld, E. Jorgensen, and J. Kastrup
Coronary angiography transiently increases plasma pro-B-type natriuretic peptide
Eur. Heart J.,
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F. Hartmann, M. Packer, A. J.S. Coats, M. B. Fowler, H. Krum, P. Mohacsi, J. L. Rouleau, M. Tendera, A. Castaigne, J. Trawinski, et al.
NT-proBNP in severe chronic heart failure: rationale, design and preliminary results of the COPERNICUS NT-proBNP substudy
Eur J Heart Fail,
March 15, 2004;
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P.-Y. Marie, P. M. Mertes, N. Hassan-Sebbag, N. de Talence, K. Djaballah, W. Djaballah, J. Friberg, P. Olivier, G. Karcher, F. Zannad, et al.
Exercise release of cardiac natriuretic peptides is markedly enhanced when patients with coronary artery disease are treated medically by beta-blockers
J. Am. Coll. Cardiol.,
February 4, 2004;
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R. Latini, S. Masson, I. Anand, M. Salio, A. Hester, D. Judd, S. Barlera, A. P Maggioni, G. Tognoni, J. N Cohn, et al.
The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT
Eur. Heart J.,
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A. Kjaer, J. Appel, P. Hildebrandt, and C. L. Petersen
Basal and exercise-induced neuroendocrine activation in patients with heart failure and in normal subjects
Eur J Heart Fail,
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M.R Cowie, P Jourdain, A Maisel, U Dahlstrom, F Follath, R Isnard, A Luchner, T McDonagh, J Mair, M Nieminen, et al.
Clinical applications of B-type natriuretic peptide (BNP) testing
Eur. Heart J.,
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K. Hryniewicz, A. S. Androne, A. Hudaihed, and S. D. Katz
Comparative Effects of Carvedilol and Metoprolol on Regional Vascular Responses to Adrenergic Stimuli in Normal Subjects and Patients With Chronic Heart Failure
Circulation,
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[Abstract]
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R. Latini, S. Masson, I. Anand, D. Judd, A. P. Maggioni, Y.-T. Chiang, M. Bevilacqua, M. Salio, P. Cardano, P. H.J.M. Dunselman, et al.
Effects of Valsartan on Circulating Brain Natriuretic Peptide and Norepinephrine in Symptomatic Chronic Heart Failure: The Valsartan Heart Failure Trial (Val-HeFT)
Circulation,
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B. A. Groenning, J. C. Nilsson, P. R. Hildebrandt, A. Kjaer, T. Fritz-Hansen, H. B.W. Larsson, and L. Sondergaard
Neurohumoral prediction of left-ventricular morphologic response to {beta}-blockade with metoprolol in chronic left-ventricular systolic heart failure
Eur J Heart Fail,
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K. Sedlacek, M. Fischer, J. Erdmann, C. Hengstenberg, S. Holmer, S. Kurzinger, M. Muscholl, A. Luchner, G. A. Riegger, H.-W. Hense, et al.
Relation of the G Protein {beta}3-Subunit Polymorphism With Left Ventricle Structure and Function
Hypertension,
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C. Zugck, A. Haunstetter, C. Kruger, R. Kell, D. Schellberg, W. Kubler, and M. Haass
Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure
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J. Lindenfeld, A. D. Robertson, B. D. Lowes, M. R. Bristow, and for the MOCHA Investigators
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B. A. Groenning, J. C. Nilsson, L. Sondergaard, A. Kjaer, H. B.W. Larsson, and P. R. Hildebrandt
Evaluation of impaired left ventricular ejection fraction and increased dimensions by multiple neurohumoral plasma concentrations
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M. G. Andreassi, S. Del Ry, C. Palmieri, A. Clerico, A. Biagini, and D. Giannessi
Up-regulation of 'clearance' receptors in patients with chronic heart failure: a possible explanation for the resistance to biological effects of cardiac natriuretic hormones
Eur J Heart Fail,
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[Abstract]
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J. A. Smith, D. Bruusgaard, E. Bodd, and C. Hall
Relations between medical history, clinical findings and plasma N-terminal proatrial natriuretic peptide in patients in primary health care
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[Abstract]
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A. F. M. van den Heuvel, P. H. J. M. Dunselman, T. Kingma, P. Verhorst, F. Boomsma, W. H. van Gilst, and D. J. van Veldhuisen
Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade
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J.M Cruickshank
Beta-blockers continue to surprise us
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Effects of Metoprolol CR in Patients With Ischemic and Dilated Cardiomyopathy : The Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study
Circulation,
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[Abstract]
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Abstract
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